Nuclear receptors are hormone-regulated transcription factors that control many key aspects of normal metazoan reproduction, differentiation, and homeostasis; aberrant nuclear receptors are causal factors in a variety of human endocrine and neoplastic disorders. The ultimate goal of this proposal is to better understand how nuclear receptors participate in signal transduction in normal cells, and the lesions in this process that lead to disease. Many nuclear receptors exhibit bimodal transcriptional properties, and can either repress or activate gene expression. We and others have identified a family of "corepressors" that physically associate with nuclear receptors, recruit additional proteins, and mediate transcriptional repression. Many signals that impact on nuclear receptor function manifest their effects through changes in corepressor recruitment or function. We propose to continue our research into how the actions of nuclear receptors are mediated through these corepressors. Although focused on repression, aspects of these studies will also touch on the functions of coactivators, and on additional effectors and regulators of nuclear receptor function. Our experiments will address specific aspects of five broad questions: Specific Aim 1. Why do different nuclear receptor isoforms differ in the ability to interact with corepressor and mediate repression? Specific Aim 2. How does the nature of target DNA influence repression? Specific Aim 3. How does the binding of different hormone ligands regulate repression? Specific Aim 4. How do non-ligand signal transduction pathways regulate repression? Specific Aim 5. How do defects in corepressor function lead to disease? The results from these experiments will contribute to a better understanding of the molecular basis behind nuclear hormone receptor function in both the normal and diseased organism. More broadly., we anticipate that our studies of corepressor action will help clarify the more general phenomenon of eukaryotic transcriptional repression.